Sci. Aging Knowl. Environ., 20 April 2005
Vol. 2005, Issue 16, p. nf31
[DOI: 10.1126/sageke.2005.16.nf31]


Defining the Diet

Single ingredient might hold key to calorie restriction's benefits

R. John Davenport

Cutting out the chocolate cake won't improve your physique if you keep gorging on hamburgers. But a new study reveals that limiting one dietary component--the amino acid methionine--extends the lives of mice that eat otherwise full meals. Withholding methionine could tap into mechanisms similar to those exploited by calorie restriction (CR), suggesting that people might reap the rewards of drastically reduced food intake with a less severe diet.

The study reveals that "you can achieve at least part of the effects of caloric restriction by taking down just this one amino acid," says evolutionary biologist Linda Partridge of University College London. "That suggests that it's not calories; it's the restriction of particular nutrients that is responsible for the full effect." However, other researchers hold firm to the idea that calories are crucial.

For at least 70 years, researchers have known that slashing calories by 30% to 40% extends the lives of mice and rats (see Masoro Review). However, despite considerable effort, they don't grasp why limiting food intake delays death. Evidence suggests that the ascetic diet might, for example, bolster stress defenses, encourage a longevity-promoting hormone profile, or fine-tune metabolism. Researchers have also found that less sweeping dietary changes can impart long life. For instance, in 1993 scientists discovered that a diet lean in methionine, an amino acid not crafted by the body, delays death in rats. However, no one knew whether this treatment simulates CR or if other organisms would also benefit. In new work, pathologist Richard Miller of the University of Michigan, Ann Arbor, and colleagues served mice methionine-meager cuisine and assessed their physiology.

The team transferred 6-week-old female mice to chow that contained either a full dose of methionine or 23% of the normal amount and studied the animals for the rest of their lives. At first, many of them died, perhaps because the animals weren't getting enough methionine to subsist. So the team bumped up the methionine content to 28% of normal when the mice were 4 months of age and 33% at 6 months. These modifications improved mice survival. The oldest animals in the control group lasted 1144 days, whereas those on the restricted diet persisted more than 100 days longer, suggesting that cutting back on methionine extends the lives of mice as well as rats. In a 5-day test on a small group of animals, the researchers found that mice on the low-methionine diet ate at least as much as did control animals, suggesting that the rodents didn't live longer because they consumed less, says Miller.

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The next South Beach? Mice on low-methionine cuisine (right) live longer and appear healthier than do normally fed animals. [Credit: R. Miller, University of Michigan]

Next, the researchers found that the blood of mice fed methionine-poor grub contained less of the hormones insulin, insulin-like growth factor 1, and thyroid hormone--molecules known to wane in CR animals and in long-lived genetic dwarf rodents. In addition, the animals harbored smaller quantities of blood glucose after fasting, a sign of healthy metabolism. The diet also boosted the activity of a gene know to crank on in CR animals and long-lived dwarfs.

Further experiments revealed that curbing methionine intake protects against age-related disease and damage, as does CR. Mice on the modified vittles developed less severe cataracts and had fewer of a particular type of immune cell that accumulates with age than did normally fed rodents. They also suffered less liver trauma when the researchers injected their bellies with toxic doses of acetaminophen, which incites oxidative mayhem.

"The most significant thing is that the hormone profile ... looks very much like [that of] a calorically restricted mouse," says gerontologist Steven Austad of the University of Texas Health Science Center (UTHSC) in San Antonio. "Whether that means that this is really just another form of caloric restriction or something more general than that is really up in the air." Although mice in both groups ate about the same quantity of food during the 5-day test, those on the methionine-poor diet weighed substantially less than controls for most of their lives, he notes. "That suggests to me that they aren't just methionine restricted, they're also calorically restricted--not in the sense that they are eating less, but in the sense that they're absorbing less."

Physiologist Roger McCarter of Pennsylvania State University, University Park, says that assessing food intake alone isn't a good test of whether an animal is calorie restricted. Previous studies conflict on whether CR animals eat more or less per gram of body weight, he says. For instance, CR mice allowed to exercise eat more food for their body weight than do nonexercising controls, yet they still live long. To really get at whether mice on low-methionine fare are experiencing CR, researchers need to rigorously measure how much food animals take in, how much they excrete, and how active they are, says McCarter. "If they eat the same but weigh less, where are those extra calories going?" he asks. Miller agrees that the animals might not be absorbing all of the food they're consuming. The mice produce more urine than normal, he says, suggesting that they are excreting some of what they're eating; the animals would need the extra liquid to dilute breakdown products from the surplus nutrients.

Regardless of whether the methionine-rationed animals are short on calories, some experts say that reduced intake of the amino acid is unlikely to be responsible for the effects of CR. The life extension spurred by small amounts of methionine is "about half of what you usually expect for caloric restriction," says physiologist Arlan Richardson, also of UTHSC. And some say that previous studies already disprove the possibility that methionine is crucial for CR to work. "The evidence is clear that it's indeed calories," says gerontologist Ed Masoro, a professor emeritus at UTHSC now living in Charleston, South Carolina. "We ruled out reduction in methionine in 1989." In those experiments, they served rats traditional CR fare or the same meal with extra protein; both groups of animals lived equally long, suggesting that a dearth of a particular amino acid wasn't responsible for long life when calories are limited. However, it left open the question of whether depleting an individual amino acid would mimic CR when calories are plentiful.

Although Masoro doesn't agree that dearth of a particular nutrient underlies CR-powered life extension, he says that CR and methionine restriction might tap into similar pathways. Masoro theorizes that reducing methionine amounts and cutting calories might extend life by stressing animals mildly, thereby activating survival mechanisms--an idea known as hormesis (see "Stress for Success"). "If all essential amino acids behave the same, it would build a very strong case" for hormesis, he says. Some data already support this idea. Studies from the late 1980s showed that mice and rats that consumed less tryptophan--another essential amino acid--also gain extra time.

Additional tests are needed to determine how much CR and the low-methionine diet overlap. "Nutrient-sensing pathways are all sensitive to specific molecules," says Partridge, "and as far as we know, there's no [physiological] mechanism that just measures calories." Under CR, animals might sense the absence of a few key components that normally reflect the general abundance of food. Methionine might be a particularly robust indicator, she adds. It's the first amino acid in every protein, so monitoring methionine amounts would provide a good measure of whether amino acid intake is adequate. However, methionine restriction might extend life in a completely different way, says Miller. For instance, reducing methionine quantities might limit production of toxic methionine derivatives, boost quantities of the antioxidant glutathione, or alter gene activity by changing the pattern of methyl groups on DNA, a process that depends on methionine-related molecules. Clarifying the similarities and differences between CR and methionine restriction might reveal a palatable way to garner long life.

April 20, 2005

R. John Davenport is an associate editor of SAGE KE. To cover his bases, he's going to ask the butcher for low-cal turkey that is methionine- and tryptophan-free.

  1. R. A. Miller et al., Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell, 13 April 2005 [e-pub ahead of print]. [Abstract] [Full Text]
Citation: R. J. Davenport, Defining the Diet. Sci. Aging Knowl. Environ. 2005 (16), nf31 (2005).

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